title: Exogenous OX40 stimulation during lymphocytic choriomeningitis virus infection impairs follicular Th cell differentiation and diverts CD4 T cells into the effector lineage by upregulating Blimp-1.
abstract: T cell costimulation is a key component of adaptive immunity to viral infection but has also been associated with pathology because of excessive or altered T cell activity. We recently demonstrated that the TNFR family costimulatory molecule OX40 (CD134) is critically required to sustain antiviral T cell and Ab responses that enable control of viral replication in the context of chronic lymphocytic choriomeningitis virus (LCMV) infection. In this study, we investigated whether reinforcing OX40 stimulation through an agonist Ab had the potential to prevent LCMV persistence. We observed that anti-OX40 injection early after LCMV clone 13 infection increased CD8 T cell-mediated immunopathology. More strikingly, OX40 stimulation of virus-specific CD4 T cells promoted expression of the transcriptional repressor Blimp-1 and diverted the majority of cells away from follicular Th cell differentiation. This occurred in both acute and chronic infections, and resulted in dramatic reductions in germinal center and Ab responses to the viral infection. The effect of the OX40 agonist was dependent on IL-2 signaling and the timing of OX40 stimulation. Collectively, our data demonstrate that excessive OX40 signaling can result in deleterious consequences in the setting of LCMV infection.
authors.affiliation: Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037;
authors.forename: Tobias
authors.initials: T
authors.lastname: Boettler
authors.forename: Youn Soo
authors.initials: YS
authors.lastname: Choi
authors.forename: Shahram
authors.initials: S
authors.lastname: Salek-Ardakani
authors.forename: Yang
authors.initials: Y
authors.lastname: Cheng
authors.forename: Friedrich
authors.initials: F
authors.lastname: Moeckel
authors.forename: Michael
authors.initials: M
authors.lastname: Croft
authors.forename: Shane
authors.initials: S
authors.lastname: Crotty
authors.forename: Matthias
authors.initials: M
authors.lastname: von Herrath
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D002522:Chlorocebus aethiops; D018858:Germinal Center / Q000276:immunology; D007376:Interleukin-2 / Q000378:metabolism; D008216:Lymphocytic Choriomeningitis / Q000276:immunology*; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000074462:Positive Regulatory Domain I-Binding Factor 1; D053262:Receptors, OX40 / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D014157:Transcription Factors / Q000096:biosynthesis*; D014709:Vero Cells; D014779:Virus Replication
chemical_list: D007376:Interleukin-2; C513258:Prdm1 protein, mouse; D053262:Receptors, OX40; D014157:Transcription Factors; D000074462:Positive Regulatory Domain I-Binding Factor 1